This Center application is being submitted in response to the National Institution of Health's Program Announcement "Centers for the Neuroscience of Mental Disorders (CNMD)." The overall aim of the Center is a co-ordinated investigation of the neurobiology of molecular biology of inherited risk factors in schizophrenia. Although there is extensive epidemiological evidence that schizophrenia has a heritable component, the illness itself does not have a Mendelian segregation and precisely what biological dysfunction is inherited is unknown. Because of these uncertainties, no simple neurobiological or molecular biological approach is likely to readily define the heritable elements in either genetic or neuronal terms. Investigation is further complicated by the lack of an animal model and by the general prohibition against invasive experiments in human brain. Therefore, this Center is designed to pursue a series of collaborative investigations in which various approaches converge to attempt to identify the neuronal defect and its genetic basis. The Center employs neurobiological techniques in humans and human tissue--patients and their families, in oculo transplants, and most mortem tissue--to characterize the nature of the inherited neuronal dysfunctions, models their neuronal mechanisms in animals, and then uses several different molecular biological strategies to determine whether genes coding for or otherwise linked to these functions are abnormal in schizophrenics. Thus, as neurobiological hypotheses are formulated, they are confirmed or refuted by genetic analysis. The process is interactive, so that information from genetic investigations is also used to refine the identification of the phenotype, which in turn supports further genetic analysis.